Endoscopic ultrasound guided interventional procedures

Abstract

Endoscopic ultrasound (EUS) has emerged as an important diagnostic and therapeutic modality in the field of gastrointestinal endoscopy. EUS provides access to many organs and lesions which are in proximity to the gastrointestinal tract and thus giving an opportunity to target them for therapeutic and diagnostic purposes. This modality also provides a real time opportunity to target the required area while avoiding adjacent vascular and other structures. Therapeutic EUS has found role in management of pancreatic fluid collections, biliary and pancreatic duct drainage in cases of failed endoscopic retrograde cholangiopancreatography, drainage of gallbladder, celiac plexus neurolysis/blockage, drainage of mediastinal and intra-abdominal abscesses and collections and in targeted cancer chemotherapy and radiotherapy. Infact, therapeutic EUS has emerged as the therapy of choice for management of pancreatic pseudocysts and recent innovations like fully covered removable metallic stents have improved results in patients with organised necrosis. Similarly, EUS guided drainage of biliary tract and pancreatic duct helps drainage of these systems in patients with failed cannulation, inaccessible papilla as with duodenal/gastric obstruction or surgically altered anatomy. EUS guided gall bladder drainage is a useful emergent procedure in patients with acute cholecystitis who are not fit for surgery. EUS guided celiac plexus neurolysis and blockage is more effective and less morbid vis-à-vis the percutaneous technique. The field of interventional EUS is rapidly advancing and many more interventions are being continuously added. This review focuses on the current status of evidence vis-à-vis the established indications of therapeutic EUS.

Key Words: Endosonography; Pancreatic pseudocyst; Celiac plexus; Choledochostomy; Cholecystostomy; Photochemotherapy; Abdominal abscess; Common bile duct; Pancreatic duct; Endoscopic ultrasound-guided fine needle aspiration

Core tip: Therapeutic endoscopic ultrasound (EUS) has found role in management of pancreatic fluid collections, biliary and pancreatic duct drainage in cases of failed endoscopic retrograde cholangiopancreatography, drainage of gallbladder, celiac plexus neurolysis/blockage, drainage of mediastinal and intra-abdominal abscesses and collections and in targeted cancer chemotherapy and radiotherapy. The field of interventional EUS is rapidly advancing and many more interventions are being continuously added. This review focuses on the current status of evidence vis-à-vis the established indications of therapeutic EUS.

Endoscopic ultrasound (EUS) is an important diagnostic and therapeutic technique in the field of gastroenterology. The ability to visualise and access organs in vicinity of the gastrointestinal tract has opened this exciting field with many interventional EUS procedures now overtaking conventional approaches for treatment of various gastrointestinal diseases. While advances have been made in all aspects of diagnostic and therapeutic EUS, the present review will focus on advances in therapeutic EUS and use of EUS in drainage of pancreatic collections, celiac plexus neurolysis, biliary/pancreatic duct drainage, and in the drainage of intra-abdominal abscesses.

EUS GUIDED DRAINAGE OF PANCREATIC FLUID COLLECTIONS

Pancreatic fluid collections

Acute and chronic pancreatitis can be complicated by collections of varying nature composed of pancreatic juice and varying amounts of necrotic debris in patients with acute necrotising pancreatitis[1]. The morphological characteristics of pancreatic collections complicating acute pancreatitis seem to change with time and the amount of solid necrotic debris lessens with time[2]. Pancreatic fluid collections need to be drained if they get infected or become symptomatic and cause abdominal pain, gastric outlet obstruction or biliary obstruction. Radiological, surgical and endoscopic approaches have been used to drain pancreatic collections[3,4]. Broadly, collections needing drainage early in the course of illness when a wall has not yet formed are drained via percutaneous interventions while endoscopic drainage is feasible late in the course when wall has formed[5]. The distinction between the types of collection is important before drainage as the nature and outcome of drainage depend to a large part on the amount of solid debris present in the pancreatic fluid collections (PFCs)[6-8]. While non-necrotic collections have an excellent outcome with endoscopic drainage, the fate of necrotic collections is not as good. In one report while treatment success was 93.5% in pseudocyst drainage it was much lower at 63.2% for drainage of walled off necrosis[9]. Morphologic features like size and amount of debris predict the number of procedures needed as increasing size and amount of debris predict more number of procedures[8].

Endoscopic drainage vs EUS-guided drainage

While many centres continue to perform pancreatic pseudocyst drainage endoscopically, there is some evidence to suggest that EUS-guided drainage may be preferable. Two randomised trials have indicated a higher technical success especially in non-bulging lesions (Table 1)[10,11]. EUS-guided drainage is preferable in certain other clinical scenarios like presence of portal hypertension, collaterals around the collection, and presence of calcification in the wall[14,15]. A meta-analysis of available studies suggest that the technical success rates are higher for EUS guided drainage but the short term and long term results appeared to be similar[12]. In one of the report comparing the endoscopic and EUS guided drainage, median hospital stay was reported as similar with the two modalities[11]. Both reports indicate that the procedure time was not significantly different with either of the modality[10,11].

Table 1 Comparison between endoscopic vs endoscopic ultrasound-guided drainage of pancreatic pseudocysts.

Ref.	Patients and methods	Results
Park et al[10]	Randomised trial of conventional vs EUS guided drainage of pancreatic pseudocysts (n = 60)	EUS guided drainage has higher technical success (94% vs 72%). EUS preferable in non-bulging collections. Complications and pseudocyst resolution similar
Varadarajulu et al[11]	RCT of conventional vs EUS guided drainage (n = 15 each)	Higher technical success in EUS guided procedure (100% vs 33%) with lesser complications
Kahaleh et al[12]	Conventional drainage in bulging pseudocysts and absence of portal hypertension vs EUS guided in rest (n = 99)	No differences in short term or long term success and similar complications
Barthet et al[13]	Algorithm based approach of transpapillary (for small), EUS guided (nonbulging) or Conventional drainage of pseudocysts	EUS guided approach needed for atleast half of the patients

EUS: Endoscopic ultrasound; RCT: Randomized controlled trials.

EUS guided drainage of PFCs

The drainage using EUS is done by using a linear echoendoscope which is advanced into the stomach or duodenum. The window is assessed using colour Doppler for any regional vascularity as well as the distance between the gastrointestinal tract wall and the cyst is measured. A 19 gauge EUS fine needle aspiration (FNA) is utilised to access the collection and contents aspirated for visual assessment as well as for analysis (cultures, amylase and carcinoembryonic antigen levels). Following this a guidewire is coiled into the cyst cavity and the tract is dilated[6,7,16]. Following this various modifications are available for the drainage of PFCs including single or multiple stentings, multistep procedure with initial nasocystic drain followed by placement of stent or insertion of fully covered self-expanding metallic stents[17]. Also, after resolution of PFC, removal of transmural stents may result in recurrence of PFCs[18]. Long term indwelling plastic stents, especially in patients with disconnected duct, is a preferred approach currently in these patients[19]. Multiple authors have reported good results of EUS guided drainage and Table 2 shows important studies reporting outcomes with EUS-guided drainage of PFCs[20-36].

Table 2 Endoscopic ultrasound guided drainage of pancreatic fluid collections (excluding self expanding metallic stents).

Ref.	Number	Outcome
Giovannini et al[20]	35 patients: 15 pseudocyst and 20 WON	Technical success: 94.3%
		Clinical success: 88.5%
Hookey et al21]	116 patients (51 EUS guided transmural drainage)	Technical success: 93.8%
		Clinical success: 90.6%
Krüger et al[22]	35 patients (both pseudocysts and abscess)	Technical success: 94%
		Clinical success: 88%
Antillon et al[23]	33 patients: all pseudocysts	Technical success: 94%
		Clinical success: 90%
Lopes et al[24]	62 procedures: 36 pseudocysts and 26 abscesses	Technical success: 94%
		Clinical success: 84.3%
Ardengh et al[25]	77 patients with sterile PFCs	Technical success: 94%
		Clinical success: 91%
Varadarajulu et al[26]	60 patients: 36 pseudocyst and 24 with abscess/WON	Technical success: 95%
		Clinical success: 93%
Ahn et al[27]	47 patients with pseudocyst	Technical success: 89%
		Clinical success: 100%
Will et al[28]	132 patients: 31 pseudocysts (n = 32), 115 abscesses/WON	Technical success: 97%
		Clinical success: 96%
Seewald et al[29]	70 patients: including pseudocyst, WON, abscess	Technical success: 97.5%
		Clinical success: 83%
Puri et al[30]	40 patients with pseudocyst	Technical success: 100%
		Clinical success: 97%
Kato et al[31]	67 patients with pseudocyst	Technical success: 88%
		Clinical success: 83%
Künzli et al[32]	108 patients	Technical success: 97%
		Clinical success: 84%
Siddique et al[33]	87 patients with WON	Technical success: 99%
		Clinical success: 73.5%
Hocke et al[34]	30 patients with WON	Technical success: 96.7%
		Clinical success: 83.4%
Jürgensen et al[35]	35 patients with WON	Technical success: 100%
		Clinical success: 97%
Yasuda et al[36]	57 patients with WON	Technical success: 100%
		Clinical success: 75%

WON: Walled off necrosis; EUS: Endoscopic ultrasound; PFCs: Pancreatic fluid collections.

Innovations

Use of metallic stents: Use of self expanding metallic stents (SEMS) has recently been advocated as they may provide a better drainage because of wider diameter and thus a quicker resolution of the symptoms[37]. Various removable stents with anti-migration features have been introduced for drainage of PFCs. Fully covered stents with dumbbell like shape have been introduced which provide lumen apposition and have lesser chances of migration[38]. Various innovations like insertion of plastic pigtail stents to prevent migration have been employed with these stents[39]. The major benefit of SEMS is likely to be in walled off necrosis (WON) as they may provide ease of repeated access for necrosectomy, however this remains to be proven in prospective studies. Table 3 depicts the studies where metallic stents were used in management of PFCs.

Table 3 Use of metallic stents for endoscopic ultrasound guided drainage of pancreatic fluid collections.

Ref.	Population	Stent	Design	Outcome
SEMS
Talreja et al[17]	18 patients with PFCs	FCSEMS (biliary stent)	Prospective cohort	95% success
Belle et al[40]	4 patients with WON	PCSEMS	Case series	100% clinical success
Fabbri et al[41]	22 patients with infected PFCs	FCSEMS (biliary)	Case series	77% clinical success
Penn et al[39]	20 with PFCs	FCSEMS (biliary) with plastic pigtail	Case series	Technical success 100%, clinical success 85%
Weilert et al[42]	18 patients with PFCs	FCSEMS	Case series	Clinical success in 78%
LACSEMS
Shah et al[43]	Pseudocyst and WON (n = 33)	AXIOS (EUS guided in 30/33)	Prospective cohort	91% technical success, 93% resolution of PFC
Walter et al[44]	46 patients WON and 15 pseudocyst	AXIOS stent	Prospective cohort	Technical success: 98%, clinical success: 93% in pseudocyst and 81% in WON
Gornals et al[45]	9 patients with PFCs	AXIOS	Case series	Technical success in 88% and 100% clinical success
Itoi et al[46]	15 patients with pseudocysts	AXIOS	Retrospective case series	100% clinical success
Yamamoto et al[37]	9 PFCs, 5 pseudocyst and 4 WON	FCSEMS (Nagi stent)	Retrospective case series	77.8% clinical success
ESOPHAGEAL SEMS
Sarkaria et al[47]	17 patients with WON	Esophageal FCSEMS	Retrospective case series	88% clinical success

SEMS: Self expanding metallic stents; PFCs: Pancreatic fluid collections; FCSEMS: Fully covered SEMS; WON: Walled off necrosis; LACSEMS: Lumen apposing covered SEMS.

Non-fluoroscopic drainage: It has been demonstrated that EUS-guided drainage is feasible even without fluoroscopic control[6,48]. Seicean et al[48] have demonstrated the utility of EUS in drainage of PFCs in 24 patients and documented complete resolution in 83.3% cases. However difficulty arose in PFCs with thickened wall for which fluoroscopic control was recommended by the authors. We have also demonstrated the efficacy of EUS in draining non-bulging PFCs in 20 patients in absence of fluoroscopic control. Only one patient needed percutaneous intervention amongst these 20 patients[6]. In another report of EUS guided drainage of 22 patients with PFCs, drainage was technically feasible in 19 patients even in absence of fluoroscopy. Success after single procedure was noted in 59% patients[49].

Creation of multiple drainage routes: In management of walled off necrosis, creation of a single enteral opening may not provide adequate drainage of the collection. In this regard it may be better to have multiple access sites into the cavity which may help in improving drainage and irrigation of the cavity. Dual modality drainage involving percutaneous and endoscopic drainage simultaneously has been advocated for achieving this end[50]. A purely endoscopic procedure: EUS guided multi transluminal gateway technique has been evaluated and reported to have a high success (91.7%) vis-à-vis convention drainage (52.1) in a non-randomised study[51]. Prospective reports validating this approach are awaited.

Forward viewing echoendoscope: A multicentre randomised trial reported use of a forward viewing echoendoscope for drainage of PFCs. The technical success rates, mean procedure times, ease of access and complication rates were similar to the oblique-viewing echoendoscope indicating lack of any benefit with use of forward viewing echoendoscope for drainage of PFCs[52].

Others

Access to the cavity may be difficult in patients with thick wall between the gastric/duodenal lumen and the cavity and therefore the tract may be difficult to dilate. To overcome this use of wire guided bent needle knife to obtain a wide access has been used[53]. A double guidewire technique utilising a double lumen catheter has been advocated to avoid the hassle of repeated need for cannulation of pseudocyst for placing multiple endoprosthesis[54]. A modification of the dual-lumen biliary brush catheter has also been used to place multiple guidewires into the cyst cavity and thereby allowing placement of multiple stents[55]. A novel exchange free access device has also been used for EUS guided drainage of PFCs and has an inner trocar for puncture and an outer dual balloon for dilatation of the tract reducing the need for multiple exchanges[56,57]. Numerous other innovations like use of hydrogen peroxide and streptokinase have been used but comparative data vis-à-vis control group is not yet available[58,59].

Drainage of PFCs is an important therapeutic application of EUS with excellent technical and clinical outcomes. We believe that merely dividing walled off PFCs into pseudocysts and WON may be too simplistic and it would be better to have three subgroups including acute postnecrotic pseudocyst (< 10% solid debris), walled off liquid necrosis (10%-40% solid content) and walled off solid necrosis (> 40% solid debris) as this has implications on management and success of endoscopic drainage[60]. We have previously shown that the amount of necrosis predicts the therapy needed in PFCs. Whilst those with < 10% debris need only one session of drainage, those with 10%-40% solid debris needed ≥ 2 sessions and the group with even higher (> 40%) debris needed direct endoscopic debridement or surgical necrosectomy[8]. Based on this, we follow an algorithmic approach (Figure 1) for management of PFCs at our institution.

Figure 1 Proposed endoscopic treatment algorithm for walled off pancreatic necrosis. EUS: Endoscopic ultrasound; MRI: Magnetic resonance imaging; PFC: Pancreatic fluid collection; SEMS: Self expanding metallic stents.

EUS GUIDED BILIARY ACCESS

Endoscopic retrograde cholangio-pancreaticography (ERCP) is the standard approach to drain an obstructed biliary tract but may fail due to a number of factors like inaccessible papilla or a failure to cannulate it. In these situations, radiological or surgical drainage is needed. EUS guided biliary drainage is emerging as an alternative to a failed ERCP[16]. EUS guided approaches include transmural drainage (hepaticogastrostomy or choledochoduodenostomy), a rendezvous procedure or an antegrade approach[61]. EUS guided transluminal drainage (EUS-TLD) is achieved by bile duct puncture from the stomach or the duodenum using EUS-FNA needle. Occasionally choledochoantrostomy or hepaticoesophagostomy has also been described for achieving biliary drainage[62-64]. After obtaining a cholangiogram a guidewire is placed into the biliary system and the tract dilated followed by insertion of stent to achieve drainage of biliary system into the stomach or the duodenum. While duodenal station is used to achieve access into the common bile duct, gastric station allows access to the left lobe intrahepatic biliary radicals[61]. Access to right sided biliary system has also been described[65]. Table 4 depicts the major reports of EUS guided transluminal access to biliary system. EUS guided rendezvous is achieved by creation of a temporary access to the biliary tree using EUS guided approach in patients with failed cannulation but with accessible papilla. The guidewire is then negotiated across the obstruction into the duodenum through the papilla and is then retrieved using snare and thereby providing a conduit for further ERCP[61]. This approach is, therefore, useful in failed ERCP but accessible papilla. The approach from the stomach and first part of duodenum is considered to be stable but the ampullary direction of guidewire is achieved best from the stomach and second part of duodenum[61]. Table 5 depicts the major reports of EUS guided rendezvous procedures and their outcomes. EUS guided antegrade approach is the use of temporary EUS guided access created from the duodenum or stomach for placement of stents or balloon dilatation without the scope reaching the papilla. The reported success rate for this procedure is 77% and the complication rate is 5%, however large studies are lacking[61].

Table 4 Endoscopic ultrasound guided transluminal biliary drainage.

Ref.	Number	Etiology	Technical success	Clinical success	Complication rates
Takada et al[66]	26 17 CCD, 6 HG, 2 CCA, 1 HJ	Malignant	90.6%	100%	20.7%
Kawakubo et al[67]	64 CCD: 44 HG: 20	Malignant	95%	100%	19%
Prachayakul et al[68]	21 CCD: 6 HG: 15	Malignant	95.2%	90.2%	9.5%
Hara et al[69]	18 CCD	Malignant	94%	94%	11%
Song et al[70]	15 CCD	Malignant	86.7%	100%	23.1%
Kim et al[71]	13 CCD: 9 HG: 4	Malignant	92.3%	91.7%	30.7%
Park do et al[72]	57 CCD: 26 HG: 31	Both benign and malignant	96.5%	89%	20%
Komaki et al[73]	15 CCD	Malignant	93%	100%	26.7%
Hara et al[74]	18 CCD	Malignant	94%	100%	17%
Khashab et al[64]	20 HG: 3 CCD: 15 HE: 2	Malignant	95%	86.3%	10%
Vila et al[75]	60 HG: 34 CCD: 26	Both benign and malignant	64.7% and 86.3%	63.2%	15.1%
Attasaranya et al[76]	25 HG: 16 CCD: 9	Both benign and malignant	77%	96%	35%

CCD: Cholecystoduodenostomy; HG: Hepaticogastrostomy; CCA: Cholescystoantrostomy; HJ: Hepaticojejunostomy.

Table 5 Endoscopic ultrasound rendezvous procedures for biliary drainage.

Ref.	Number	Technical success	Clinical success	Complications
Khashab et al[64]	13 (EH: 11, IH: 2)	100%	100%	15%
Tarantino et al[77]	4 (EH: 4)	50%	100%	13%
Dhir et al[78]	20	100%	100%	15%
Dhir et al[79]	17 TH, 18 EH	100% for EH and 94.1% for TH	100%	Higher for TH vs EH
Park do et al[80]	20 (14 IH and 6 EH)		80%	10%
Kawakubo et al[81]	14 (9 EH and 5 IH)	100%	100%	14%
Dhir et al[82]	58 (all EH)	-	98%	3.4%
Iwashita et al[83]	40 (31 EH and 9 IH)		73%	13%

EH: Extrahepatic; IH: intrahepatic.

EUS-TLD is associated with significant complications including perforation, bile leak, bleeding, and stent dysfunction or migration. The use of EUS-TLD has also been reported to be as efficacious as transpapillary drainage in patients with previous duodenal stents with a higher stent patency rate with EUS-TLD[84]. SEMS are preferred over plastic stents as they provide a larger diameter and therefore are likely to remain patent for longer periods and the risk of bile leaks is likely to be less with SEMS. SEMS also make a reinsertion of stent easier as stent can be placed into the previous SEMS[85]. Both EUS-TLD and placement of duodenal SEMS in patients with obstructive jaundice and duodenal obstruction due to unresectable periampullary lesions has been reported as a single step procedure with use of linear echo-endoscope[86].

EUS guided approaches have also been compared with percutaneous approach for biliary drainage. In a randomised study comparing percutaneous and EUS guided approaches in 25 patients with unresectable biliary obstruction, the technical success, clinical success, cost and complications were similar amongst both the groups suggesting that either could be used as an alternative for biliary drainage[87]. However a recent report comparing 51 patients who underwent percutaneous transhepatic biliary drainage (PTBD) with 22 patients who underwent EUS-TLD indicated that the technical success was higher for PTBD. The authors however recommended EUS-TLD as the initial procedure of choice as it needed lesser re-interventions reducing costs of therapy as also a lower adverse event rate[88]. In a similar report where 50 patients were retrospectively evaluated success of internal stenting as well as complication rates were more favourable in the EUS-TLD group. While internal stenting could be achieved in 92% patients in EUS-TLD group, it could be achieved only in 46% of PTBD group[89]. Amongst EUS guided approaches, transhepatic access seems to increase the risk of complications vis-à-vis transduodenal access of the biliary tree[78]. An approach has been suggested for the use of various EUS guided methods for achieving biliary drainage in different clinical settings. If ampulla is inaccessible, EUS-TLD is the initial choice. If papilla is accessible rendezvous should be attempted but if it is not possible to cross the lesion/stricture then EUS-TLD can be undertaken. Antegrade approach may be better suited for surgically altered anatomy where the procedure is needed for benign lesions[61].

EUS GUIDED GALL BLADDER DRAINAGE

The emergent gall bladder drainage is usually done radiologically but availability of EUS has made it possible to drain the gall bladder endoscopically. This may be indicated in situations like acute cholecystitis in patients who are unsuitable for surgery and have not improved with antibiotics[90]. In a systematic review of endoscopic drainage of gallbladder using nasogallbladder drainage in 194 patients and gallbladder stenting in 127 patients the technical success rates were 81% and 96%, clinical success rates were 75% and 88% and complication rates were 3.6% and 6.3%, respectively[90,91]. In a randomised study of patients with acute cholecystitis who were assigned to undergo either an EUS guided drainage or a percutaneous drainage of gall bladder the technical success rates were similar as were the complication rates suggesting that EUS guided approach is feasible for gall bladder drainage with outcomes comparable to the percutaneous approach[92]. Major reports (> 10 patients) on EUS guided drainage of gall bladder are shown in Table 6.

Table 6 Endoscopic ultrasound guided gall bladder drainage for acute cholecystitis.

Ref.	Number	Technical success	Clinical success	Complications
Jang et al[92]	30	97%	100%	7%
Lee et al[93]	9	100%	100%	11%
Song et al[94]	8	100%	100%	37%
Jang et al[95]	15	100%	100%	13%
de la Serna-Higuera et al[96]	13	85%	85%	15%

Gall Bladder drainage can be achieved by use of either plastic or metallic stents or use of naso-gallbladder drains[94,95]. The complications may include bile leak, perforation and pneumo-peritoneum. In a report evaluating long term outcomes in 56 patients with acute cholecystitis who had underwent EUS guided gallbladder drainage the stent patency was 86% over 3 years. Four patients had late adverse events including distal stent migration in 2 patients and acute cholecystitis due to stent occlusion in 2 patients. The stent occlusions were treated endoscopically[97]. A single step procedure for insertion for lumen opposing metallic stent using AXIOS system has also been reported[98]. EUS guided gallbladder drainage has also been used as an approach for drainage in unresectable pancreatic cancer with use of anti-migratory fully covered metallic stents[99]. EUS guided gall bladder drainage may be of value in situation where a percutaneous procedure is dificult or more risky (presence of ascites and coagulopathy) but comes at an increased risk associated with sedation in patients with various comorbidities and the risk of bile leak.

EUS GUIDED PANCREATIC DUCT DRAINAGE

EUS guided pancreatic ductal (PD) drainage may be indicated for patients with failed transpapillary drainage like in failed cannulation of non-negotiable strictures in chronic pancreatitis or pancreatic fistulae or pancreaticogastric or pancreaticojejunal stenosis after pancreatic surgery[100]. Both trans-enteric stenting and rendezvous procedures can be accomplished after EUS guided access to the pancreatic duct has been obtained. Once an access has been achieved using EUS-FNA needle and a guidewire is placed into the PD, and dilatation of the tract is done. SEMS are not used to drain the pancreatic duct for the associated risk of obstructive pancreatitis due to blockage of the side branches of the pancreatic duct. Complications associated with EUS guided PD drainage include leakage of pancreatic juice, pancreatitis, perforation or bleeding[101,102]. In a systematic review of 9 studies including 205 patients the pancreatic duct drainage was successful in 58%-100% with clinical success in 74% and a complication rate of 20%[102]. Success rates were lesser in a nationwide retrospective study form Spain[75]. Both rendezvous and transenteric drainage has been reported to have similar efficacy although it may be difficult to do a rendezvous in tight strictures[103,104]. The EUS guided PD access can be utilised for taking brushings to confirm malignancy in pancreatic stricture[105]. Access may be easier to obtain in dilated duct[104]. Some data is available about long term clinical success which indicates that at a median follow-up of 37 mo pain relief was present in 72% patients[106]. Another report indicated complete pain relief in 83% of patients[107]. It is important to suspect underlying malignancy in those with lack of pain relief[108]. Anterograde pancreatic drainage including stricture dilatation and removal of stone has also been reported[109,110]. To summarise EUS guided pancreatic duct drainage can be of use in rescue management of failed ERCP or in patients with surgically altered anatomy but the technique is still evolving and better accessories are needed.

USE OF EUS IN MANAGEMENT OF MALIGNANT DISEASE

Brachytherapy

Recently EUS guided brachytherapy has also been evaluated with radioactive seeds being placed into the tumour of interest under EUS guidance with the help of linear echoendoscope[111,112]. The most popular radioactive seeds are Iodine 125, palladium 103 and iridium 192. In pancreatic cancers where the cells divide quite rapidly, iodine is the radioactive material of choice as it has got a long half life of 60 d. The radioactive spill over the region of interest is definitely an issue of concern but in human tissue the penetration distance of the radiation into surrounding tissue is very small. The seeds of EUS guided brachytherapy were sowed by Sun et al[111] with their study in pigs. Sun et al[111] published the use of iodine 125 in unresectable pancreatic cancer in 15 patients. The result revealed a median survival of 10.6 mo with 27% patients having partial tumour response[111]. In another study in 22 patients with advanced pancreatic cancer where combination of gemcitabine and Iodine 125 brachytherapy was used, the overall survival rate didn’t improve[112].

Fiducial marker placement

For external beam radiation to the cranium, bony landmarks are used for guiding the therapy while in intraabdominal malignancy fiducial markers are placed inside the tumour for guiding therapy. These markers are radioactive spheres, coils or seeds. Earlier fiducials were placed under surgical or radiological guidance but with advent of interventional EUS, these fiducials can be placed under EUS guidance also. Pishvaian et al[113] reported EUS guided fiducail placement in 13 patients with technical success achieved in 11/13 patients. An average of 3-4 fiducials were placed in each patient. There have been multiple studies where EUS guided fiducials have been placed successfully in pancreatic cancers, esophageal cancers and neuroendocrine tumours[114-116]. To compare the 2 types of fiducials a study was conducted in 39 patients with advanced pancreatic cancer. Traditional fiducials of 5 mm length and viscoil fiducials of 10 mm length were compared. It was observed that traditional fiducials had better visibility scores as compared to viscoil fiducials and the migration rate between the two types of fiducials was similar[117].

EUS guided ethanol ablation

Ethanol causes cell death by membrane lysis, vascular occlusion and protein denaturation and has been used for ablation of solid and cystic lesions of thyroid, liver, adrenals, etc. EUS guided ethanol ablation has been used recently for ablation of pancreatic lesions, neuroendocrine tumors (NETs) and metastatic abdominal lesions. EUS guided fine needle injection therapy using alcohol is safe and better than percutaneous approach as it is delivers alcohol to target tissue with more accuracy, identify surrounding structures and perform injection therapy in real time monitoring.

In a study by Gan et al[118] including 25 patients with pancreatic cysts who underwent ablation with variable concentrations of alcohol (5%-80%), the results revealed complete resolution in 8 patients and epithelial ablation in 5 patients who underwent surgery. In another study ethanol injection was compared with saline injection alone. In this study 25/42 patients were initially treated with alcohol and rest 17 with saline. After 3 mo, patients in both the groups were treated with ethanol injection. The results showed that 80% ethanol injection resulted in a greater decrease in size as compared to saline injection. Nine patients who were followed up for 2 years had no recurrence of cyst[119]. In another study of 42 patients with cystic tumours of the pancreas who were initially injected with 99% ethanol followed by paclitaxel. Complete resolution was achieved in 29 patients. No complications were observed[120]. EUS guided ethanol ablation of pancreatic neuroendocrine tumours has been reported in patients who are not good candidates for surgery either because of age or comorbidities. There have been published reports where even multiple NETs have been injected with alcohol and ablation has been achieved with patient remaining symptom free post injection. But there is a risk of recurrence and metastasis. So long term follow up studies are required to adequately define the role of ethanol ablation in NETs[121-125].

Multiple metastatic lesions have also been ablated with EUS guided ethanol injection but its role in these situations need to assessed in larger studies. These include hepatic metastases from carcinoma colon, pelvic lymph nodal metastases from rectal cancer, left adrenal metastases from non-small cell carcinoma lung, hepatic metastases from pancreatic carcinoma and ablation of a gastrointestinal stromal tumour in a patient whose comorbidities precluded surgery[126-129].

Delivery of antitumor agents

Pancreatic carcinoma has got a poor response to chemotherapeutic agents and radiation. In presence of locally advance disease and borderline resectability, neoadjuvant chemotherapy has been tried, but it carries a poor response rate as the tumour is hypovascular and produces a desmoplastic reaction around it leading to poor delivery of drugs. So various local antitumour agents have been tried in patients with advanced pancreatic carcinoma for palliation and in locally advanced lesions for downstaging before surgery (Table 7).

Table 7 Antitumour agents, their composition and area of use.

Name of the agent	Drug	Ref.	Reported use
CYTOIMPLANT	Allogenic mixed lymphocyte culture	Chang et al[130]	Advanced pancreatic cancer
TNFerade	cDNA expressing TNF-α (adenovector)	Hecht et al[131], Chang et al[132] and Citrin et al[133]	Pancreatic, esophageal and rectal cancer
ONY X-015	Adenovirus	Mulvihill et al[134]	Advanced pancreatic cancer
Oncogel	Paclitaxel and ReGel	Linghu et al[135], Matthes et al[136] and Vukelja et al[137]	Pancreatic, esophageal cancer
Gemcitabine	Gemcitabine	Levy et al[138]	Advanced pancreatic cancer
DC’s	Dendritic cells	Irisawa[139], Hirooka et al[140]	Advanced pancreatic cancer

The problem with all these studies is that they were small and all these agents in this role are still in experimental stage. So we need much more large prospective studies before these techniques can be put into clinical practice.

Tumour ablation

Thermal injury leading to coagulation necrosis has been the principle of radiofrequency ablation (RFA). This principle has been exploited for treatment of solid tumours like hepatocellular carcinoma (HCC) and liver metastases. Percutaneous, open or laparoscopic approach have been associated with morbidity and mortality. Recently EUS guided RFA has been performed under real time guidance in porcine models. Studies of EUS RFA done in porcine models have used the technique for ablation of lymph nodes and pancreatic lesions[141,142]. Majority of pigs tolerated the procedure well except for few complications.

EUS photodynamic therapy

Photodynamic therapy is another modality for tumour ablation. Here a photosensitizer drug is injected and application of light is done to the area of interest. The tumour cells are killed by direct cytotoxic effects, vascular changes and inflammatory reaction[143,144]. A study in porcine models where EUS guided photodynamic therapy has been done to liver, pancreas and kidney showed that 100% necrosis was seen in pancreas only[145].

EUS guided laser therapy

It is an evolving technique and recently a case was reported where EUS guided laser ablation of a left lobe HCC was performed using 22 G needle and patient was followed up for 2 mo with no recurrence of the lesion[146].

EUS-GUIDED INRAABDOMINAL ABSCESS DRAINAGE

EUS guided internal drainage of abdominal and pelvic abscesses has emerged as an alternative to traditional percutaneous drainage. Abscesses in areas close to the gastrointestinal lumen including mediastinum, lesser sac, perihepatic and subphrenic space, and pelvis can be drained using EUS guidance. The procedure involves the usual steps described earlier for PFC drainage: access using 19 G EUS-FNA needle, use of guidewire, dilatation of tract and placement of drainage catheter or pigtail stents. The suggested dilatation diameters for esophagus is 6 mm, for colon and jejunum is 6-8 mm, for duodenum 8-10 mm and in stomach 8-15 mm[147]. Table 8 shows various reports of EUS guided drainage of pelvic abscesses.

Table 8 Endoscopic ultrasound guided drainage of pelvic abscesses.

Ref.	Number	Site	Technical success	Clinical success	Complications
Hadithi et al[148]	8	Abdominal (pelvic)	100%	100%	0
Puri et al[149]	30	Pelvic (4 prostatic)	93.3%	83.5%	0
Ramesh et al[150]	38	11 transcolonic, 27 transrectal	100%	87%	10.5%
Puri et al[151]	14	Pelvic	100%	93%	0
Varadarajulu et al[152]	25	Pelvic	100%	96%	0
Giovannini et al[153]	12	Pelvic	100%	75%	25%

Mediastinal abscesses have also been drained under EUS guidance including placement of lumen opposing stents[154,155]. A few reports have also involved aspiration of splenic abscess in setting of pancreatitis[156,157]. Liver abscess have also been drained using EUS guidance and placement of lumen apposing stent has also been done[158,159].

EUS GUIDED CELIAC PLEXUS BLOCK

Percutaneous celiac plexus neurolysis (CPN) has been used for management of pain in pancreatic cancer and sometimes for chronic pancreatitis. EUS guided CPN has emerged as a more effective technique in recent times[160]. Using the linear echoendoscope at the level of gastroesophageal junction the aorta is located and celiac artery traced. While alcohol is used to obtain CPN, bupivacaine is used for celiac plexus block (CPB). Although triamcinolone is often added to bupivacaine but a randomised study found no benefit with addition of triamcinolone[161]. The average efficacy of CPB for pain relief is around 3 mo. Transient hypotension and diarrhea may occur as side effects of the procedure. The EUS guided technique avoids passage through the vertebrae and muscles at the back as required for a CT guided celiac block and therefore unlikely to have related adverse events like paraparesis[162]. Interestingly, ganglion cells have now been visualised on EUS and it may be better to target ganglions directly[163,164]. In a randomised trial comparing CPN with celiac ganglia neurolysis (CGN), the positive response was higher in the CGN group (73.5% vs 45.5%). Half of the patients in CGN group obtained complete relief vis-à-vis 18% in CPN group[165].

Multiple comparative reports have emerged which have compared radiologic vs EUS guided CPN. EUS guided CPN provided a more long lasting pain relief (30% up to 24 wk) while with CT guided CPN only 12% had some relief at 12 wk[166]. In a trial comparing one vs two injections for pain relief during CPN, no incremental benefit in pain relief was observed with two injections[167]. EUS guided CPB was more efficacious for pain relief in patients with chronic pancreatitis in a randomised comparison with percutaneous CPB[168]. Only a subset of patients with EUS guided CPN obtain complete pain relief and the duration of pain relief is variable. The predictors of pain relief are not established. Also the benefit of performing CPN rather than CPB in chronic pancreatitis is not clear[169].

It is apparent that the availability of interventional EUS has allowed gastroenterologists to make forays into areas which traditionally remained the domain of surgeons and interventional radiologists. With further improvements in accessories and development of EUS-natural orifice transluminal endoscopic surgery, the endosonologist will have to do multiple roles[170].